(2024) 22:333
Sun et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03554-1

BMC Medicine

RESEARCH

Open Access

Overall and cause-specific mortality
among patients diagnosed with gastricprecancerous lesions in Sweden between 1979
and 2014: an observational cohort study
Yawen Sun1,2, Li Yin2, Dariush Nasrollahzadeh Nesheli2, Jingru Yu2, Joar Franzén2 and Weimin Ye2*

Abstract
Background The Correa’s cascade, encompassing chronic non-atrophic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia, represents the well-recognized pathway for the development of non-cardia gastric cancer.
Population-based studies on all-cause and cause-specific mortalities among patients with gastric lesions in Correa’s
cascade are scarce.
Methods We compiled a cohort of 340 744 eligible patients who had undergone endoscopy with biopsy for nonmalignant indications during the period 1979–2011, which was followed up until 2014. Standardized mortality ratios(SMRs) with 95% confidence intervals (CIs) provided estimation of the relative risk, using the general Swedish population as reference. Cox regression model was used to estimate hazard ratios (HRs) of death for internal comparison.
Results A total of 306 117 patients were included in the final analysis, accumulating 3,049,009 person-years of followup. In total 106,625 deaths were observed during the study period. Compared to the general population, excess
risks of overall mortality were noted in all subgroups, with SMRs ranging from 1.11 (95% CI 1.08–1.14) for the normal
mucosa group to 1.54 (95% CI 1.46–1.62) for the dysplasia group. For cause-specific mortalities, mortality from gastriccancer gradually increased along Correa’s cascade, with excess risk rising from 105% for patients with chronic gastritis
to more than 600% for the dysplasia group. These results were confirmed in the comparison with the normal mucosa
group. For non-cancer conditions, increased death risks were noted for various diseases compared to the general
population, especially among patients with more severe gastric precancerous lesions. But the results were confirmed only for “infectious diseases and parasitic diseases”, “respiratory system diseases”, and “digestive system disease”,
when using the normal mucosa group as reference.
Conclusions Increased mortality from gastric cancer suggests that early recognition and intervention of gastric precancerous lesions probably benefit the patients. Excess mortality due to non-cancer conditions should be interpretedwith caution, and future studies are warranted.
Keywords Gastric precancerous lesions, Overall mortality, Cause-specific mortality, Cancer, Non-cancer conditions*Correspondence:
Weimin Ye
weimin.ye@ki.se
Full list of author information is available at the end of the article© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which
permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to theoriginal author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images orother third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line
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regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of thislicence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Sun et al. BMC Medicine(2024) 22:333

Background
The Correa’s cascade, comprising a sequential progression from chronic non-atrophic gastritis to atrophic
gastritis, intestinal metaplasia, and dysplasia, is a wellrecognized pathway for the development of non-cardia
gastric cancer [1]. Some patients with these lesions will
eventually develop invasive gastric adenocarcinoma if
appropriate intervention or treatment is not taken [2, 3].
Globally, 1 in 12 cancer deaths is caused by gastric cancer, making it the third leading cause of cancer death [4].
And the prognosis of gastric cancer patients remains dismal. In the USA, no significant improvement in survival
was reported for patients with non-cardia gastric adenocarcinoma during the past 20 years [5]. The distributionof tumor stage at gastric cancer diagnosis and 5-year
survival both worsened over time among patients in the
Netherlands [6].
Our earlier study examined stomach cancer incidence
among patients with different mucosal lesions in Sweden. The results indicated patients with lesions along
Correa’s cascade had an increasingly higher incidence ofgastric cancer in comparison to that of the general population [7]. In 2020, Boreiri et al. conducted a prospective
study, involving endoscopic examination and biopsy on
1011 residents in Adabir, Iran, and revealed that gastricprecancerous lesions, including atrophic gastritis andintestinal metaplasia, significantly increased the risk ofdeath from gastric cancer [8]. However, a comprehensive
analysis of mortality and causes of death among patientswith gastric precancerous lesions remains elusive. Arguably, the most significant indicator of health inequality
for any population group is excess mortality relative tothe general population. An understanding of the driversof excess mortality is important for patients with gastricprecancerous lesions and for those concerned with their
lifetime needs, such as family members, health professionals, and policymakers.
Starting from the 1970s, pathology departments in
Sweden have been recording the histopathological resultsfor patients undergoing gastroscopy and with tissue
biopsy. Taking advantage of these completely computerized registrations, we launched a large-scale, long-timeobservational cohort study, to describe the overall andcause-specific mortality profiles for patients diagnosed
with gastric precancerous lesions at baseline. For thesepatients, we further quantified their excess risks of death
relative to the entire Swedish population and patientswith normal gastric mucosa.
Methods
Study design

From 1979 to 1998, 24 pathology departments in Sweden built up computerized registers gradually [7]. The

Page 2 of 9collected data included patients’ national registration
numbers (unique identifiers for all Swedish residents)
along with other variables such as date, age, sex, andpathological-anatomical diagnosis utilizing the Systematized Nomenclature of Medicine Morphology (SNOMED
M) codes. Based on these registers, we created a cohort
enrolling all patients who underwent gastroscopic biopsy
for non-malignant indications. Up to Dec 31, 2014, we
identified 445,664 subjects with at least one examination record. Causes and date of death were ascertainedby cross-linkage to the Swedish Cause of Death Register. We also retrieved information from the Swedish
Death Register for double check of death date and further
cross-linked with the Swedish Emigration Register for
censoring. Linkage to the Education Register provided
information of the highest level of education achieved by
the subjects.
As described previously, we limited subjects enrolled
between 1979 and 2011, and after further exclusion,
434,337 participants remained in the cohort [9]. For
each participant, the first biopsy date was defined as
the date of enrollment in the database. We grouped thecohort members by their SNOMED M diagnosis at baseline (for detailed information please see Table S1). This
study focused on gastric mucosal status within Correa’s
cascade, categorized into normal, minor mucosal change,chronic gastritis, atrophic gastritis, intestinal metaplasia, and dysplasia. So, we further excluded patients not
in Correa’s cascade at baseline (n = 69,821) and thosewith gastric cancer at or before baseline (n = 23,772). The
study cohort finally included 340,744 eligible patients(Fig. 1). We continued follow-up until death, emigration, or the end of follow-up (Dec 31, 2014), whicheveroccurred first. We categorized deaths broadly as due
to gastric cancer, non-gastric cancers, and non-cancer
conditions. And non-cancer conditions were defined byorgan system. The diagnosis of cause-specific death usedthe corresponding International Classification of Diseases (ICD) codes (Table S2).
Statistical analysis

To measure the absolute risk of mortality, we calculated
crude death rates for gastric cancer, non-gastric cancers,
and non-cancer conditions by dividing the number ofdeaths with the observed person-years. We also calculated standardized mortality ratios (SMRs) by dividing
the observed number by the expected number of deaths,
derived by multiplying sex-, age- (in 5-year intervals),and calendar year-specific mortality rates for the general
population with the person-years at risk accrued in ourcohort. The 95% confidence intervals for the crude death
rate and SMRs were calculated assuming Poisson distribution for the number of deaths.

Sun et al. BMC Medicine(2024) 22:333

Page 3 of 9

We regularly observed a peak of mortality emerging hastily after the first gastric biopsy among the study
population probably due to undetected cancer patients,
indirectly resulting in an overestimation of the deathrisk for the study population. Therefore, to minimize theinfluence of selection bias, we chose to start follow-up
when this peak had passed. Thus, in our main analysis,
we discarded the first 2 years of observation and deaths
detected during this period.
We used hazard ratios with 95% confidence intervals, derived from the Cox proportional hazards regression model, to evaluate the association between gastricmucosal status and risks of deaths.
The time scale used was the attained age. The regression model was adjusted for age, sex, and education level,
as well as calendar year as a time-dependent covariate. The proportional hazards assumption was checked
graphically and by Schoenfeld’s partial residuals; neither of them revealed any indication of violation of thisassumption. P values less than 0.05 were considered toindicate statistical significance. The results were all analyzed using SAS statistical software, version 9.3 (Cary,
NC).

Fig. 1 Study design for stomach biopsy cohort in Sweden (1979–2014). Baseline is defined as the first biopsy identified in the database.
When multiple diagnoses were present, the most severe one
was selected

Results
After adding the required lag time of 2 years, we finallyidentified 306 117 patients whose diagnoses were classified into Correa’s cascade. Of the total patients,
44.58% were male. Mean (± SD) age at cohort entry was
56.64 ± 19.37 years. The mean duration of follow-up was
9.96 years, and 3,049,009 person-years at risk were accumulated (Table 1). Chronic gastritis comprised morethan 58% of the entire cohort, contrasted by less than
1% for dysplasia. Patients with more advanced gastricprecancerous lesions tended to be older than those withmilder lesions. Except dysplasia group, males were lessdominant in other subgroups. The normal mucosa (10.42
years) and chronic gastritis (10.38 years) group had theTable 1 Characteristics of patients enrolled in stomach biopsy cohort
Mucosal status at ­baselinea

No of participants (%)

Mean (SD) age atcohort entry (years)b% maleMean (SD) follow-up
duration (years)b

Person-yearsb

Overall

306117 (100.00)

56.64 (19.37)

44.58

9.96 (6.53)

3049009

Normal33052 (10.80)

46.40 (20.60)

41.18

10.42 (6.00)

344468

Minor mucosal changes

67111 (21.92)

50.03 (19.76)

40.89

9.20 (6.21)

617522Chronic gastritis

177647 (58.03)

58.30 (18.18)

46.60

10.38 (6.74)

1843404

Atrophic gastritis

14981 (4.89)

60.25 (18.49)

41.36

9.69 (6.59)

145233

Intestinal metaplasia

11058 (3.61)

66.22 (14.78)

47.67

6.99 (4.61)

77338

Dysplasia

2268 (0.74)

65.52 (14.78)

51.94

9.28 (6.70)

21044

a

Defined as the first biopsy identified in the database. When multiple diagnoses were present, the most severe one was selectedbCalculated after exclusion of first 2 years of follow-up

Sun et al. BMC Medicine(2024) 22:333

longest mean follow-up duration, while the intestinal
metaplasia group had the shortest (6.99 years).
A total of 106 625 deaths occurred during follow-up.
Table 2 presents the distribution of death cases alongwith crude mortality rate and SMR, from normal mucosa
to dysplasia groups. For overall mortality, all subgroups
showed an increased risk compared to the general
population, with SMRs ranging from 1.11 for the normal mucosa group to 1.54 for the dysplasia group. For
gastric cancer death, the mortality rate in the normalgroup was 16.26 × ­10−5 (95% CI 12.51–21.13), without
showing a statistically, significantly increased death risk
(SMR 1.18, 95% CI 0.87–1.49) compared to the Swedish general population. Then, the mortality increased
stepwise along Correa’s cascade. For patients withchronic gastritis, the mortality was 54.19 × ­10−5 (95%
CI 50.94–57.66), corresponding to a 105% excess risk
(95% CI 92–118%). For the dysplasia group, the mortality increased to 237.60 × ­10−5 (95% CI 180.08-313.49),
which corresponded to a SMR of 7.01 (95% CI 5.06–
8.95). For non-gastric cancers, modest excess mortalities
were also evidenced among all subgroups, ranging from
8% (atrophic gastritis, 95% CI 1–14%) to 53% (dysplasia,
95% CI 35–72%). For non-cancer conditions, a conspicuously elevated risk of death from “infectious and parasitic
disease” was observed among the patients with dysplasia (SMR 2.56, 95% CI 1.73–3.40), whereas moderately
increased mortality risks varied from 26 to 48% in othergroups. For “Endocrine, nutritional and metabolic disease”, excess mortality was from 30 to 81%, showing anirregular upward trend among subgroups, with dysplasia(SMR 1.81, 95% CI 1.23–2.39) having the highest excess
death risk. The generally increased mortalities from “respiratory system disease” were observed in all subgroups,
among which patients with dysplasia (SMR 1.91, 95% CI
1.57–2.25) had the most prominently increased risk ofdeath. Compared with the Swedish population, patientswith dysplasia (SMR 2.23, 95% CI of 1.65–2.81) had thehighest risk of death from “digestive system diseases”,
followed by patients with minor mucosal changes (SMR
1.93, 95% CI 1.79–2.08) and chronic gastritis (SMR 1.92,
95% CI 1.85–1.98).
To further explore the potential association between
grade of lesion and death risk, we separately calculated
hazard ratios (HRs) with 95% CIs across gastric precancerous lesion groups by cause of death, using the normalgroup as reference, to minimize the influence of selection
bias (Table 3). For the all-cause death, there was a 1.09
(minor mucosal changes, 95% CI 1.06–1.13) to 1.33-fold(dysplasia, 95% CI 1.26–1.42) increased risk of death inpatients with gastric precancerous lesions compared to
the normal mucosa group, while HR for the atrophic gastritis group was non-significant (1.02, 95% CI 0.99–1.06).

Page 4 of 9

Gastric cancer death strongly correlated with having dysplasia, with a nearly sixfold increased death risk (HR 5.85,
95% CI 3.95–8.66). Less conspicuous excesses, but still
substantial and statistically significant, were also seen ingroups of intestinal metaplasia (HR 2.63, 95% CI 1.82–
3.79), atrophic gastritis (HR 2.03, 95% CI 1.45–2.85), andchronic gastritis (HR 1.71, 95% CI 1.29–2.26). For nongastric cancer deaths, the mortality risk of patients withminor mucosal changes (HR 1.13, 95% CI 1.06–1.21),
chronic gastritis (HR 1.07, 95% CI 1.01–1.13), intestinal
metaplasia (HR 1.14, 95% CI 1.05–1.25), and dysplasia(HR 1.34, 95% CI 1.18–1.54) was higher than that of thenormal mucosa group. For non-cancer conditions, thedeath risk of “infectious diseases and parasitic diseases”
was appreciably raised in the dysplasia group (HR 2.02,
95% CI 1.38–2.95). Most notably, the mortality risk ofpatients with chronic gastritis (HR 1.13, 95% CI 1.03–
1.25), intestinal metaplasia (HR 1.23, 95% CI 1.06–1.42),
and dysplasia (HR 1.48, 95% CI 1.20–1.81) were significantly elevated for “respiratory system disease” when
they were compared to that of normal mucosa group. For
death from “digestive system disease”, the HRs (95% CIs)
were 0.80 (0.66–0.96) and 1.36 (1.02–1.81) for groups ofatrophic gastritis and dysplasia, respectively, showing
opposite trends in death risks. Remarkably, for “Endocrine, nutritional and metabolic disease”, HRs (95% CIs)
across the 5 groups of gastric lesions were all without statistical significance.

Discussion
In this nationwide pathology-based cohort study, weused two complementary measures to explore the association between abnormal gastric mucosal histology andall causes of death among the Swedish population. We
found an excess mortality rate due to diseases involvingorgans and systems boundless of the gastrointestinal system (GI) associated with an abnormal stomach biopsy
2 years after a gastroscopy.
An attractive feature of cohort studies is the capability they provide to examine a range of health outcomes such as follow-up for mortality from different
causes of death. The cohort in this study is not definedby population or health condition. Alternatively, an
index event of histology reporting of gastric biopsy
defines the current cohort. In this cohort, having a
stomach histology report is the index health event,
not the health indication for which esophago-gastroduodenoscopy (EGD) was prescribed. Under this setting, those who underwent EGD without performing agastric biopsy would not be included. Also, this study
is blind toward the comorbidities in the esophagus or
duodenum and their possible pathology reports during the same EGD session when gastric biopsy wasSun et al. BMC Medicine(2024) 22:333

Page 5 of 9

Table 2 All-cause and cause-specific mortalities among subjects undergoing endoscopy, stratified by mucosal status at b
­ aselinea
NormalMinor mucosal changes

Chronic gastritis

Cause ofdeath

No of deathb

Crude mortality ratec

SMR (95% CI)d No of deathb

Crude mortality ratec

SMR (95% CI)d No of deathb

Crude mortality ratec

SMR (95%CI)d

All cause

6190

1796.98

1.11 (1.08–1.14) 14628

2368.83

1.26 (1.24–1.28) 74044

4016.70

1.28(1.27–1.29)

Cancers1490

432.55

1.11 (1.05–1.17) 3512

568.73

1.28 (1.24–1.32) 15212

825.21

1.24(1.22–1.26)

Gastric
cancer56

16.26

1.18 (0.87–1.49) 156

25.26

1.59 (1.34–1.84) 999

54.19

2.05
(1.92–2.18)

Non-gastriccancers1434

416.291.11 (1.05–1.16) 3356

543.46

1.27 (1.23–1.31) 14213

771.02

1.21(1.19–1.23)

Non-cancer
conditions

4700

1364.421.11 (1.08–1.14) 11116

1800.10

1.25 (1.23–1.28) 58833

3191.541.29(1.28–1.30)

Infectious
and parasitic
disease

121

35.13

1.26 (1.03–1.48) 299

48.42

1.48 (1.31–1.65) 1283

69.60

1.38
(1.30–1.45)

Endocrine,
nutritional,
and metabolic
disease

178

51.67

1.30 (1.11–1.49) 422

68.34

1.48 (1.34–1.62) 1987

107.791.45(1.39–1.52)

Mentaland behavioral
disorder

235

68.22

0.81 (0.71–0.91) 584

94.57

0.96 (0.88–1.04) 3170

171.971.05(1.01–1.08)

Nervoussystem198

57.48

1.09 (0.94–1.24) 444

71.90

1.18 (1.07–1.29) 1899

103.02

1.15(1.09–1.20)

Circulatory
system2444

709.501.03 (0.99–1.07) 5899

955.27

1.18 (1.15–1.21) 33057

1793.26

1.23(1.22–1.25)

Respiratory
system469

136.151.24 (1.13–1.35) 1069

173.111.35 (1.26–1.43) 5924

321.361.42(1.38–1.45)

Digestive
system294

85.35

1.67 (1.48–1.86) 700

113.36

1.93 (1.79–2.08) 3353

181.891.92(1.85–1.98)

Genitourinary system

90

26.13

1.22 (0.96–1.47) 253

40.97

1.61 (1.41–1.81) 1220

66.18

1.43
(1.35–1.51)

Symptoms, signs,
and ill-definedconditions

155

45.00

0.94 (0.79–1.09) 345

55.87

1.01 (0.91–1.12) 1848

100.25

1.11(1.06–1.16)

Cause ofdeath

No of deathb

Atrophic gastritis
Crude mortality ratec

SMR (95% CI)d No of deathb

Intestinal metaplasia
Crude mortality ratec

SMR (95% CI)d No of deathb

Dysplasia
Crude mortality ratec

SMR (95%CI)d

All cause

6197

4266.95

1.17 (1.14–1.20) 4240

5482.44

1.25 (1.21–1.29) 1326

6301.12

1.54(1.46–1.62)

Cancers

1218

838.66

1.12 (1.06–1.19) 874

1130.111.28 (1.19–1.36) 314

1492.121.75(1.56–1.94)

Gastric
cancer98

67.48

2.31 (1.85–2.77) 67

86.63

2.88 (2.19–3.57) 50

237.607.01(5.06–8.95)

Non-gastriccancers1120

771.181.08 (1.01–1.14) 807

1043.47

1.22 (1.14–1.31) 264

1254.52

1.53(1.35–1.72)

Non-cancer
conditions

4979

3428.30

1.18 (1.14–1.21) 3366

4352.33

1.24 (1.20–1.29) 1012

4809.00

1.48(1.39–1.57)

Infectious
and parasitic
disease

112

77.12

1.27 (1.04–1.51) 90

116.371.35 (1.07–1.63) 36

171.07

2.56(1.73–3.40)

Endocrine,
nutritional,
and metabolic
disease196

134.96

1.57 (1.35–1.78) 115

148.701.38 (1.12–1.63) 37

175.82

1.81(1.23–2.39)

Mentaland behavioral
disorder308

212.071.06 (0.94–1.17) 219

283.171.02 (0.88–1.15) 50

237.601.10(0.80–1.41)

Nervoussystem172

118.43

1.11 (0.95–1.28) 112

144.820.96 (0.78–1.14) 31

147.311.26(0.82–1.71)

Circulatory
system2879

1982.34

1.16 (1.12–1.20) 1907

2465.80

1.25 (1.19–1.30) 547

2599.33

1.36(1.25–1.47)

Sun et al. BMC Medicine(2024) 22:333

Page 6 of 9

Table 2 (continued)
Respiratory
system464

319.491.20 (1.09–1.31) 353

456.44

1.48 (1.33–1.63) 121

574.991.91(1.57–2.25)

Digestive
system202

139.091.28 (1.10–1.45) 152

196.54

1.53 (1.29–1.78) 57

270.86

2.23(1.65–2.81)

Genitourinary system

103

70.92

1.29 (1.04–1.54) 63

81.46

1.24 (0.93–1.54) 22

104.541.66(0.97–2.35)

Symptoms, signs,
and ill-definedconditions

156

107.410.98 (0.83–1.14) 102

131.890.88 (0.71–1.05) 22

104.540.89(0.52–1.26)

aDefined as first biopsy identified in database. When multiple diagnoses were present, the most severe one was selectedbFirst 2 years of observation and corresponding events were excludedc

Per 100,000 person-yearsdObserved to expected number of death cases, based on age (5-year strata), sex, and calendar year (5-year strata) specific mortality rates in total Swedish population.
Ninety-five percent confidence intervals of SMRs were calculated by assuming that observed death occurrence followed a Poisson distribution

taken. Likewise, multimorbidity in other organs was
not considered, which may potentially introduce someselection bias toward diseases or treatments whichcause gastric mucosal inflammation and anemia suchas cardiovascular diseases and accompanying NSAID
or anticoagulant administration [10]. Mortality due todiagnostic or therapeutic EGD complications has noeffect on final results because the first 2-year mortality
was not included in the analysis.
People with a family history of gastric diseases andcancer may seek or be referred more often to an endoscopy unit. In this cohort, a portion of the excess mortality rate might not be a biological effect of abnormal
gastric mucosa but would instead be an effect of personal
concern on the detection of gastrointestinal problems.
By selecting the most advanced stage based on Correa’s model as an index event at the start of the followup, we fixed the cohort by blocking the possibility of
movement of individuals between chronic exposuregroups during the follow-up. Hypothetically, the earlysteps of Correa’s model are reversible upon efficient H.
pylori eradication. Clinically, active chronic gastritis isconsidered a lifelong condition without treatment. Prospective studies have shown that low-grade dysplasia
may regress up to 60% of cases, whereas 10–20% progress to high-grade dysplasia [11]. In our sensitivity test
among 21% of repeated EGD, progression and regression in gastric mucosal status were not pronounced
for two ends of the range (normal and dysplasia) [7].
Collectively, at worst, this study design would underestimate the effect size of dysplasia on the mortality
rate. In contrast, due to probable exposure dynamics,
our analysis may overestimate the effect size of minor
mucosal changes on the outcomes.
Exposure in this cohort was defined based on thesequence of gastritis, atrophy, intestinal metaplasia, anddysplasia which was first popularized by Correa as a progressive model for gastric adenocarcinoma development.

H. pylori is the most common cause of chronic gastritis
and initiation of Correa’s cascade. Since microscopy is
the least reliable method for detecting H. pylori infection,accurate data on H. pylori status was unavailable. As aresult, it is probable that a proportion of individuals categorized as normal mucosa group would be H. pylori positive. Of note, non-H. pylori chronic gastritis also occurs
not infrequently and is associated with proton pumpinhibitors (PPI) use. This condition may dilute the effectsize of the observed association between gastric mucosal
status and mortality when the normal mucosa group wasconsidered as a reference in the analysis. Another indirect
evidence for the possibility of admixture of the normalgroup with H. pylori-positive or other esophageal or duodenal comorbidities is the higher risk of mortality due todigestive diseases among the normal mucosa group in thiscohort in comparison with the general population.
Generally, histology does not yield equal precision forthe diagnosis of gastritis, atrophy, intestinal metaplasia,
and dysplasia. Based on pathology, three types of chronic
gastritis are recognizable: [1] Diffuse antral gastritis
which is usually due to H. pylori infection and could be
accurately diagnosed through histology examination ofa biopsy, [2] autoimmune metaplastic atrophic gastritis,and [3] metaplastic atrophic gastritis which develops inthe course of chronic gastritis. During chronic inflammation of the stomach, the rate of cell loss may exceed theability of stem cells to replace lost cells and mucosa thins.
This phenomenon is often accompanied by metaplasia,
and if associated with chronic inflammation is termed
chronic atrophic gastritis or gastric atrophy.
Histologic diagnosis of atrophy is challenging; due tothe lack of clarity in atrophy definition and severity (someconsider metaplasia as an essential part of atrophy diagnosis) [12, 13], and its patchy nature (which requires aminimum of two biopsies from the incisura angularis andcorpus), diagnostic accuracy of histology is imperfect inits specificity for atrophy. Other diagnostic methods suchReference

Reference

Reference

Reference

Reference

Nervous system

Circulatory system

Respiratory system

Digestive system

Genitourinary system

First 2 years of observation and corresponding events were excluded

1.14 (0.88–1.48)

1.03 (0.74–1.43)

1.05 (0.86–1.28)

1.23 (1.06–1.42)

1.15 (1.08–1.23)

0.88 (0.70–1.12)

1.22 (1.01–1.48)

1.11 (0.87–1.42)

1.13 (0.85–1.50)

1.13 (1.08–1.19)

1.14 (1.05–1.25)

2.63 (1.82–3.79)

1.20 (1.19–1.31)

1.15 (1.10–1.19)

0.32250.86950.65360.0053< 0.0001

0.3146

0.03870.38680.4056< 0.0001

0.0031< 0.0001< 0.0001< 0.0001

22

22

57

121

547

31

50

37

36

1012

264

50

314

1326

1.01 (0.64–1.58)

1.34 (0.83–2.15)

1.36 (1.02–1.81)

1.48 (1.20–1.81)

1.23 (1.12–1.35)

1.18 (0.81–1.74)

1.24 (0.91–1.69)

1.37 (0.95–1.96)

2.02 (1.38–2.95)

1.28 (1.20–1.37)

1.34 (1.18–1.54)

5.85 (3.95–8.66)

1.58 (1.35–1.73)

1.33 (1.26–1.42)

HRs (95% CI)b1.30 (1.10–1.55)

1.15 (0.92–1.44)

1.16 (1.03–1.32)

1.13 (1.03–1.25)

1.12 (1.07–1.17)

1.01 (0.86–1.18)

1.21 (1.06–1.40)

1.09 (0.92–1.28)

1.05 (0.87–1.28)

1.12 (1.09–1.16)

1.07 (1.01–1.13)

1.71 (1.29–2.26)

1.09 (1.03–1.16)

1.11 (1.08–1.15)

HRs (95% CI)b

0.98170.22910.03830.0002< 0.0001

0.39320.16760.09000.0003< 0.0001< 0.0001< 0.0001< 0.0001< 0.0001

P value

0.00260.20760.01850.0131< 0.0001

0.91690.00640.31700.6059< 0.0001

0.02500.00020.0021< 0.0001

P value

156

103

202

464

2879

172

308

196

112

4979

1120

98

1218

6197

No of deatha

Atrophic gastritis

1.21 (0.96–1.52)

1.05 (0.78–1.40)

0.80 (0.66–0.96)

0.97 (0.85–1.10)

1.05 (0.99–1.11

0.95 (0.77–1.18)

1.19 (1.00–1.41)

1.20 (0.97–1.48)

0.99 (0.76–1.29)

1.03 (0.99–1.07)

0.97 (0.90–1.05)

2.03 (1.45–2.85)

1.01 (0.94–1.09)

1.02 (0.99–1.06)

HRs (95% CI)b

0.10650.76070.01630.62250.12000.65540.05540.09840.92910.22030.4770< 0.0001

0.76450.2201

P value

Using attained age as an underlying time scale, estimated by Cox proportional hazards regression model, adjusted for sex, education status, and calendar year as a time-dependent covariate, and stratified by thepathology department

b

102

63

152

353

1907

112

219

115

90

3366

807

67

874

4240

Dysplasia
P value

1848

1220

3353

5924

33057

1899

3170

1987

1283

58833

14213

999

15212

74044

No of deatha

HRs (95% CI)b

0.04130.0441

0.06380.16770.00910.85580.11040.81620.3228< 0.0001

0.00030.20370.0001< 0.0001

No of deatha

1.23 (1.01–1.50)

1.30 (1.01–1.67)

1.15 (1.00–1.33)

1.08 (0.97–1.22)

1.07 (1.02–1.12)

1.02 (0.85–1.21)

1.14 (0.97–1.34)

1.02 (0.89–1.23)

1.12 (0.90–1.40)

1.08 (1.04–1.12)

1.13 (1.06–1.21)

1.23 (0.89–1.69)

1.13 (1.06–1.21)

1.09 (1.06–1.13)

Intestinal metaplasia

345

253

700

1069

5899

444

584

422

299

11116

3356

156

3512

14628

No of deatha

P value

Chronic gastritis
HRs (95% CI)b

Minor mucosal changes
No of deatha(2024) 22:333

aReference

Reference

Mental and behavioral disorder

Symptoms, signs, and ill-definedconditions

Reference

Endocrine, nutritional, and metabolic disease

ReferenceNon-cancer conditions

Reference

Reference

Non-gastric cancers

Infectious and parasitic disease

Reference

Gastric cancer

Reference

Reference

Genitourinary system

Cancers

Reference

Digestive system

Reference

Reference

Respiratory system

All cause

Reference

Circulatory system

NormalReference

Nervous system

Cause of death

Reference

Mental and behavioral disorder

Reference

Reference

Endocrine, nutritional, and metabolic disease

Symptoms, signs, and ill-definedconditions

Reference

ReferenceNon-cancer conditions

Infectious and parasitic disease

Reference

Non-gastric cancers

Reference

Cancers

Reference

Reference

All cause

Gastric cancer

NormalCause of death

Table 3 Hazard ratios (HRs) and 95% confidence intervals (CI) for overall and cause-specific deaths among patients with different gastric lesions compared to the normal
mucosal group

Sun et al. BMC Medicine
Page 7 of 9

Sun et al. BMC Medicine(2024) 22:333

as serology share the same imprecision [14]. Therefore,in Scandinavian populations where gastric atrophy is nothighly prevalent, the positive predictive value is low witha considerable number of false positive results. This nondifferential misclassification of dichotomous exposure(atrophy vs. non-atrophy) forces the association toward
null. It may explain the current study’s observation of anonsignificant association between gastric atrophy andmost of the specific causes of mortality which disagrees
with the observed associations of metaplasia and gastritis
with mortality risk.
Another challenging problem in the atrophy category
is the admixture of its two major types with distinguishedcauses: autoimmune and H. pylori-induced atrophy. However clinical distinction between these two types is blurred,
and a follow-up study of naive H. pylori-negative autoimmune atrophic gastritis cases did not show excess mortality from gastric cancer [15]. Yet, more studies are needed tounderstand whether the long-term behavior of the autoimmune type is distinct from H. pylori-induced atrophy.
Alternatively, atrophy can be considered as an adaptive
response in which H. pylori-sensitive mucosa is replacedby the achlorhydric environment that is better able towithstand the hostile inflammatory stress. According tothis argument, atrophy is a reversible mechanism that
postpones the adverse effect of the extension of gastritis. Atrophy breaks the chain of persistent infection.
It is observed that H. pylori do not colonize epitheliumin a stomach that has undergone intestinal metaplasticchanges following atrophy [16]. This hypothesis may partially explain the observation of no excess mortality from
non-gastric malignancies in the non-metaplastic atrophy
group. However, the change to atrophic mucosa comeswith a price; although the epithelial lining is less acidic
and less sensitive to H. pylori, mechanisms of protection
against infection are lost, encouraging overgrowth of thestomach with non-H. pylori bacteria colonizing up- or
down-stream mucosa (oral and intestinal microbiota).
Moreover, the same influences that predispose mucosa
to metaplasia, if persistent, may initiate malignant transformation in metaplastic atrophic cells. In this view, we
expect that longer follow-up time would be required toobserve excess mortality risk among non-metaplastic
atrophy groups compared to metaplasia, and gastritis.
Association between gastritis, metaplasia, and dysplasia with elevated mortality due to respiratory diseases
is of notable finding in this cohort. Respiratory diseases
represent a leading cause of mortality and morbidity.
Retrospective studies reported an inconsistent inverse
association between H. pylori and asthma and a higher
incidence of H. pylori seropositivity in chronic obstructive pulmonary disease (COPD) and chronic bronchitis. One of the potential confounders is socioeconomic

Page 8 of 9

status, which is associated with both H. pylori infection
and the risk of developing chronic bronchitis. Smoking
is another potential confounder, with a known higher
incidence of COPD and lung cancer among smokers, yet variable infection rates of H. pylori have been
observed among smokers. However, these confounding
factors do not fully explain the observed associationsin the aforementioned studies [17, 18]. Furthermore,
previous studies have examined the potential role of H.
pylori infection in the pathogenesis of respiratory diseases such as tuberculosis, cystic fibrosis, and sarcoidosis, yet contradictory results have been observed. Mostof these studies relied on small-scale case–control studies and the assessment of exposure was based on seroprevalence, which significantly hampered to draw solid
conclusions [17, 18]. The current study is by far the only
large-scale prospective study that examined this association, revealing a potential indirect link between local
consequences of H. pylori infection and respiratory diseases, meriting further investigation.
H. pylori-induced gastritis has been associated withprotein-losing gastropathy and vitamin B12 deficiency.
It may partly justify the observed elevated deaths due toendocrine and metabolic disease.
Limitations of this study

The participants in our stomach biopsy cohort were notrandomly sampled from the general population, but were
those who underwent gastroscopy and biopsy due tospecific indications. Our findings, thus, reflect a comparison of mortality risk among patients at varying Correa’s
cascade stages within a clinically assessed group and are
not directly applicable to healthy individuals without
gastroscopy. Furthermore, precancerous conditions tend
to manifest as patchy lesions, posing a certain risk offalse-negative results. However, due to the prospective
design and the 2-year latency, we essentially excluded
most cases of existing gastric cancer and serious underlying diseases at baseline. Last, we lacked information on
factors such as individual disease history, environmental
exposures, and lifestyle factors, which could potentially
aid in further risk stratification of patients.

Conclusions
The findings in this unique cohort support the notionthat the consequence of chronic inflammation of gastricmucosa is not limited to the stomach. Among extra-gastroduodenal organs and systems, excess mortality due torespiratory system disorders is of considerable notice andrequires more investigation. Among types of diseases,
malignancies (both gastric and non-gastric) were themost consistent disease types and their excess mortalities could be coherently linked to chronic inflammation

Sun et al. BMC Medicine(2024) 22:333

in the stomach. For other organs and diseases either due
to inconsistent results, a modest number of events, or the
existence of other plausible explanations, we were unable
to conclude a valid association.

Page 9 of 9

Received: 21 March 2024 Accepted: 5 August 2024

Consent for publication
Not applicable.

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Competing interests
The authors declare no competing interests.

Publisher’s Note

Abbreviations
CI	Confidence interval
EGD	Esophago-gastro-duodenoscopyHR	Hazard ratios
ICD	International Classification of Diseases
SMR	Standardized mortality ratio
SNOMED	Systematized Nomenclature of Medicine Morphology

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03554-1.
Additional file 1: Table S1. Systematized nomenclature of medicinediagnostic codes used in present cohort study. Table S2. Diagnosis codes usedin mortality analysis
Acknowledgements
We would like to thank all individuals who participated in the biopsy cohort
study and all the study team members for their exceptional efforts in datacollection and management.
Authors’ contributions
Y.S. was involved in the study design, data analysis and interpretation of theresults, and drafting the manuscript. L.Y. was involved in data analysis andrevision of the manuscript. D.N. was involved in interpretation of the results anddrafting the manuscript. J.Y. and J.F. were involved in data collection, interpretation of the results and revision of the manuscript. W.Y. was involved in conception of the study, study design, data collection, interpretation of the results, anddrafting the manuscript. All authors revised the article critically for important
intellectual content and gave final approval of the version to be published.
Funding
Open access funding provided by Karolinska Institute. This study was supported by the European Research Council (Consolidator grant, no.: 682663)
and Swedish Research Council (grant No. 2019–1429). YS was partly supportedby the Yu Jinming Academician scholarship. The funders had no role in the
conduct of this research.
Availability of data and materials
Data are not publicly available due to their containing information that could
compromise the privacy of research participants. Summary data can be madeavailable from the corresponding author on reasonable request.

Declarations
Ethics approval and consent to participate
This study was approved by the Regional Ethical Review Board in Stockholm(Dnr 2010/819–31/3; 2013/1244–32; 2015/1469–32; 2016/247–32; 2016/525–
32). This study is of register-based nature, thus informed consent was waived
by the Ethical Review Authority.

Author details
1
Shandong Cancer Hospital and Institute, Shandong First Medical University
and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
2
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet,
Stockholm 17177, Sweden.

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